Autism spectrum disorder:
A NEUROdevelopmental disorder
Sarah Spence MD PhD
Co-Director, Autism Spectrum Center
Boston Children’s Hospital
Harvard Medical School
Disclosures




I will discuss non-FDA approved medications used in
Autism Spectrum Disorder.
Member of APA DSM 5 Neurodevelopmental workgroup.
Current and past grant support from Cure Autism Now,
Autism Speaks, MIND Institute, Simons Foundation
Autism Research Initiative, Nancy Lurie Marks, NIH
One-time paid consultant for Seaside Therapeutics at a
scientific advisory meeting related to studies on a new
drug being used to treat ASD.
Objectives/Overview

Objectives




Discuss the changes to the new diagnostic criteria for
Autism Spectrum Disorder in DMS 5
Understand the medical co-morbidities in individuals with
ASD
Explain various treatment options for individuals with ASD
Overview






Epidemiology
Diagnosis
Heterogeneity
Etiological theories
Medical co-morbidities
Treatments
Epidemiology: 2014 MMWR report

14.7/1,000 (range 5.7-21.9)






Change from previous





1 in 68 children, 1 in 42 boys, 1/189 girls
largest increases were in hispanic, non-hispanic african-american,
normal IQ
no change in sex difference, age of dx (~4)
troubling racial and ethnic disparities
Methods of ascertainment are records based (medical and/or
educational)
0.4/1,000 when I was in medical school!
6.8/1,000 in 2000
8/1,000 in 2004
11.3/1,000 in 2008
Why?

We don’t know



Increased ascertainment
Earlier identification
? true prevalence increase
How do you diagnose autism
spectrum disorder?
 Diagnosis
comprised of constellation of
behavioral symptoms as defined by a group of
experts appointed by the APA (DSM 5)
 No biomarkers, no scans, no genetic tests
 Requires comprehensive developmental
history AND direct assessment/observation

Needs to include assessment of cognitive function
and adaptive skills
Common myths

He doesn’t have autism because he:
 Talks
 Looks
at me
 Interacts with me in the office
 Is interested in other kids
 Doesn’t flap or rock

He has autism because he:
 Doesn’t
talk
 Doesn’t make eye contact
 Flaps or rocks
ASD through the lifespan

Autism is a DEVELOPMENTAL disorder
 Autism
affects development
 Development affects autism

Changes over time
childhood
infancy
adulthood
adolescence
What tools do you need to make
the diagnosis?
You and the child
 YOU

 Have
to read the criteria and text.
 Have to exercise good clinical judgment.
 Have to have time
To take a thorough developmental history
 To do a behavioral observation
 Get corroborating information from other sources

Clinical Observation

Look for behaviors that should be there and
are missing
 Communicative intent
 Eye contact
 Reciprocal social interaction
(shared enjoyment,
turn taking, response to and initiation of
overtures)
 Insight into social relationships

Look for behaviors that are present and
should not be
 Repetitive behaviors
 Restricted interests
 Unusual sensory behaviors
Are there tools that can help?

Yes
 Diagnostic
criteria can be subjective
 Screening tests can bring kids to attention


M-CHAT R/F (revised with follow-up)
Social Communication Questionnaire (SCQ)
 Standardized
instruments have been extremely
helpful in research to make sure that we are all
studying the same thing


ADOS
ADI
 Standardized
instruments can help with clinical dx too
… but they are not (usually) necessary!
DSM-5 Criteria for ASD (released 5/2013)

Major changes:
 Name
change
 3 domains become 2
 Autistic Disorder, Asperger and PDD NOS
combined into Autism Spectrum Disorder
 Rett and CDD subsumed under ASD (if
appropriate)
 Adding specifiers and severity ratings
DSM-5 Criteria for ASD
In the new criteria:
A. Persistent deficits in social communication and social interaction across
multiple
contexts, asallow
manifested
by thedescription
following, currently
or by history
Examples
a
better
of
the
(examples are illustrative, not exhaustive; see text):
wholeinrange
of behaviors
seen
across
the from
1. Deficits
social-emotional
reciprocity,
ranging,
for example,
abnormal
social approach and failure of normal back-and-forth
spectrum
conversation; to reduced sharing of interests, emotions, or affect; to failure
to initiate or respond to social interactions.
Examples
include
descriptions
of higher
2. Deficits
in nonverbal
communicative
behaviors
used fororder
social
interaction,
ranging,
for example, from
poorly integrated verbal and
social
communication
skills
nonverbal communication; to abnormalities in eye contact and body
language or deficits in understanding and use of gestures; to a total lack of
mapping
of many
symptoms onto a
facial Allows
expressions
and nonverbal
communication.
3. Deficits
developing,
maintaining
understanding
given incriterion
rather
thanand
having
to see relationships,
a
ranging, for example, from difficulties adjusting behavior to suit various
behavior
socialspecific
contexts; to
difficulties in sharing imaginative play or in making
friends; to absence of interest in peers.
Allows more clinician judgment
Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright ©
2013). American Psychiatric Association. All rights reserved.
DSM-5 Criteria for ASD
B. Restricted, repetitive patterns of behavior, interests, or activities, as manifested
by at least two of the following, currently or by history (examples are illustrative,
not exhaustive; see text):
1. Stereotyped or repetitive motor movements, use of objects, or speech
(e.g., simple motor stereotypies, lining up toys or flipping objects, echolalia,
Requirement
idiosyncratic
phrases). of meeting 2 of the 4 was
necessary
for specificity
2. Insistence
on sameness,
inflexible adherence to routines, or ritualized
patterns of verbal or nonverbal behavior (e.g., extreme distress at small
Addition
ofwith
sensory
abnormalities
and greeting rituals,
changes,
difficulties
transitions,
rigid thinking patterns,
need toallowance
take same route
eat same food
every day).
for or
symptom
presence
‘by history’
3. Highly restricted, fixated interests that are abnormal in intensity or focus
(ie there in the past but no longer showing) will
(e.g., strong attachment to or preoccupation with unusual objects, excessively
capture
most patients
circumscribed
or perseverative
interests).
4. Hyper-or hypo-reactivity to sensory input or unusual interest in sensory
aspects of the environment (e.g., apparent indifference to pain/temperature,
adverse response to specific sounds or textures, excessive smelling or touching
of objects, visual fascination with lights or movement).
Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright ©
2013). American Psychiatric Association. All rights reserved.
DSM-5 Criteria for ASD
C. Symptoms must be present in the early developmental period (but may
not become fully manifest until social demands exceed limited
capacities, or may be masked by learned strategies in later life).
D. Symptoms cause clinically significant impairment in social, occupational,
or other important areas of current functioning.
E. These disturbances are not better explained by intellectual disability
(intellectual developmental disorder) or global developmental delay.
Intellectual disability and autism spectrum disorder frequently co-occur;
to make comorbid diagnoses of autism spectrum disorder and
intellectual disability, social communication should be below that
expected for general developmental level.
Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright ©
2013). American Psychiatric Association. All rights reserved.
An important note was added
This means that noone needs to
have a “re-diagnosis”
Note: Individuals with a well-established DSM-IV diagnosis
of autistic disorder, Asperger’s disorder, or pervasive
1. From disorder
a scientific
viewpoint:
developmental
not otherwise
specified should
be given
the diagnosis
of autism
There
was never
anspectrum
idea todisorder.
Individuals who have marked deficits in social
“undiagnose”
anyone
communication,
but whose
symptoms do not otherwise
meet criteria for autism spectrum disorder, should be
2.From
a practical
standpoint:
It disorder.
evaluated
for social
(pragmatic)
communication
would have been a disaster and
would overwhelm an already
overburdened system
Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright ©
2013). American Psychiatric Association. All rights reserved.
A single spectrum does not mean
lack of specificity

Specifiers were added to better describe each individual
Specify if:
With or without accompanying intellectual impairment
With or without accompanying language impairment
Associated with a known medical or genetic condition or environmental
factor
(Coding note: Use additional code to identify the associated medical or genetic condition.)
Associated with another neurodevelopmental, mental, or behavioral
disorder
(Coding note: Use additional code[s] to identify the associated neurodevelopmental,
mental, or behavioral disorder[s].)
With catatonia (refer to the criteria for catatonia associated with another
mental disorder, pp. 119–120, for definition)
(Coding note: Use additional code 293.89 [F06.1] catatonia associated with autism spectrum disorder
to indicate the presence of the comorbid catatonia.)
Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright ©
2013). American Psychiatric Association. All rights reserved.
Inclusion of severity ratings
Previously Asperger used for “milder” ASD
 Recognition that severity in one domain is
independent of the other domain
 Avoids “mild” “moderate” “severe”

Social
communication
Requires support
Requires substantial
support
Requires very
substantial support
Restricted interest
repetitive behavior
Key Concept: Heterogeneity

It is a fact
 If
you have known one person with autism … you have
known one person with autism!
 Widely varying presentations
 “High” and “Low” functioning usually refers to language
level & IQ
 Expressions of symptoms change over time

It complicates diagnosis and care tremendously
… there are implications for and interactions with
etiology, co-morbidities, treatment, outcome
Core Symptom Domains –DSM 5
Social
Communication
Deficits
Restricted
Interests
Repetitive
Behavior
AUTISM SPECTRUM DISORDER
Core Symptom Domains –DSM 5
plus SPECIFIERS Language & Cognition
Restricted
Interests
Repetitive
Behavior
Social
Communication
Deficits
ASD
Language
Disorders
Intellectual
Disability
Core Symptom Domains –DSM 5
plus associated psych symptoms
Social
Phobia
Aggression
OCD
Restricted
Interests
Repetitive
Behavior
Social
Communication
Deficits
ADHD
ASD
Language
Disorders
Intellectual
Disability
Core Symptom Domains –DSM 5
plus associated medical problems
Social
Phobia
Social
Communication
Deficits
ADHD
Aggression
OCD
Restricted
Interests
Repetitive
Behavior
Motor, sleep, GI, ASD
Epilepsy/EEG
Language
abnormalities,
Disorders
macrocephaly
Intellectual
Disability
What we know about etiology
Not one Disorder
 Not one Cause!

 Genetic
susceptibility
 Neurobiology



Abnormal synapses, excitatory/inhibitory imbalance
Abnormal cellular signaling pathways
Abnormal functional connectivity
 Immunologic
mechanisms
 Metabolic abnormalities
 Interactions amongst all of the above
CO-MORBIDITIES
Family Studies Prove Heritability

Genetic component is clear


Idiopathic autism is one of the most heritable of neuropsychiatric
syndromes
Twin studies:

Previous estimates



New large twin study from CA



MZ 42-58% for strict autism, 64-77% for ASD
DZ 13-21% for strict autism, 20-31% for ASD
Sibling recurrence risk:



MZ twin pairs: 60-70% concordance for strict autism, 90% for autism
spectrum
DZ twin pairs: same as sibling recurrence
Previous estimates 4-8%
Baby sibs studies showing ~20%
Broader phenotype in families

Language delay, dyslexia, other learning disabilities, poor social
skills, restricted interests, repetitive behaviors, other
neuropsychiatric conditions (e.g. OCD, mood disorders)
TWO theories about genetics

Rare variants
 Genetic
disorders that may be causally
related to the ASD phenotype
Named syndromes
 Microdeletions/duplications


Common variants
 Complex
genetics involving genetic variants
that are common in the population and
combine in a way to create the ASD
phenotype.
Associated Rare Diseases/Syndromes













Rett syndrome
Fragile X syndrome
Tuberous sclerosis complex
15q duplication syndrome
Prader-Willi/Angelman
Timothy syndrome
Sotos syndrome
Noonan syndrome
Joubert syndrome
Neurofibromatosis I
Hypomelanosis of Ito
Down syndrome
Williams syndrome












Congenital myotonic dystrophy
Duchenne muscular dystrophy
Velocardiofacial syndrome
Cohen Syndrome
ARX mutation
Smith-Lemli-Opitz syndrome
Cerebral Folate Deficiency
Untreated PKU
Disorders of purine metabolism
Leber’s congenital optic atrophy
Smith Magenis syndrome
Moebius Syndrome
Current testing recommendations


AAN/CNS practice parameters are out of date
American College of Medical Genetics practice
parameters call for:

FIRST TIER




Chromosomal microarray in all (yield 10%)
Fragile X in boys (yield 1-5%) (girls only if family hx or phenotype
suggestive)
Specific syndromic testing if signs and symptoms present
SECOND TIER



MECP2 girls (yield 4%)
MECP2 in any boy who has MECP2 duplication phenotype
PTEN in kids with HC >2.5 sd above the mean (yield 5%)
(Schaefer et al. 2014)
Differences in Brain Size

Macrocephaly is common
 Kanner’s
original description of autism documented
“large heads” in 5/11 patients.
 Most
studies say ~20%
 Entire
distribution shifted to the right – not just a
subgroup.
 Higher
in family members too.
 Present
early in life – early brain growth may be a
marker of autism (Courchesne et al., 2003)
Epilepsy in Autism and ASD

Increased rates of epilepsy in patients with
autism spectrum disorders (and vice versa!)
 But
- rates very variable (5-46%)
 Probably dependent on sample characteristics:

AGE


NON-IDIOPATHIC AUTISM


bimodal age of onset (childhood & adolescence).
Neurogenetic syndromes or brain injury are associated with
higher rates of epilepsy.
IQ and ?LANGUAGE skills


lower IQ increases the risk of epilepsy but even those with
normal IQ have increased risk.
language regression and poorer language skills may also
predict epilepsy although data are inconsistent.
EEG Abnormalities






No surprise that the kids with epilepsy have them
But studies started to show that some children
with autism had ISOLATED epileptiform EEGs
(without clinical seizures)
Literature in the 90’s reported rates 10-20%
More recent studies are reporting rates ~50-60%
Overnight or prolonged more sensitive than
routine studies
What to do about it is controversial
Sleep disturbance
Most data from parent report, PSG hard to do in
these kids
 Extremely common (50-80%)

 Insomnia
most common
 Delayed sleep onset
 Night awakenings
 Early morning awakening
 Reduced need for sleep

Objective measures show
 Increased
duration of stage 1 sleep
 Decreased non-REM sleep (stages 2-4)
 Shortened REM sleep
Motor impairment
Repetitive behavior or stereotypies
 Motor Delays
 Hypotonia
 Incoordination
 Gait impairment
 Apraxia
 Motor planning
 Postural control

Known metabolic disorders with ASD phenotypes












Purine disorders: adenylosuccinase deficiency, adenosine deaminase
(ADA) deficiency
Untreated PKU
Creatine disorders: arginine-glycine amidinotransferase deficiency,
guanidinoacetate methyltransferase deficiency, disorders of creatine
transport
Biotinidase Deficiency
Cerebral Folate Deficiency
Succinic semialdehyde dehydrogenase (SSADH) deficiency
Smith Lemli-Opitz Syndrome
SCAD deficiency
Infantile ceroid lipofuscinosis
Histidinemia
Urea Cycle Defects: ornithine transcarbamylase deficiency,
citrullinemia, argininosuccinic aciduria, carbamoyl phosphate synthetase
deficiency
Sanfilippo syndrome
Intellectual Disability

Previously quoted as majority of patients
 Rates
variable 40%-100%) median at 70%.
(Fombonne, JADD, 2003)


Recent MMWR data for the first time showing
<50%
Take home message: it’s variable!
 IQ
tests hard to perform, many rely heavily on
verbal abilities
 Often a big discrepancy between VIQ and NVIQ
 Huge variability among subtests.
Sensory



Unusual behaviors related to auditory, visual,
tactile senses.
Very common finding but previously not part of
diagnostic criteria.
Can be manifested by
 hyperreactivity
(sensory sensitivity) to sensory
stimulation
 hyporeactivity (sensory insensitivity) to sensory
stimulation
 By seeking out sensory stimulation through selfstimulation
Treatment
TREATMENT for ASD
• Applied Behavior
Analysis (DTT)
What is recommended?
• More naturalistic
“Educating Children with Autism” (2001)
developmental
therapies (DIR
May be found at: www.nap.edu
floortime)
Speech
• Hybrids (Denver Early
Behavioral
and
Start model, PRT,
Recommendations
for
intensive
therapy:
therapy
Language
TEACH)
•Classical articulation
therapy
•Visual communication
(PECS)
•Voice simulators (Dynavox)
•Keyboarding (actual typing)
•Group based therapies to
teach individuals how to
respond to and initiate
social interactions
•Daily living skills,
handwriting, play skills
•Sensory Integration
Therapy
20-25 hours per weekTherapy
Individualized
Trained professionals
Year round (without substantial
OccupaSocial
skills
breaks
in service)
tional
training
OT/PT/SLP
Therapy
Social skills
Behavioral supports
Complementary and Alternative
Treatments

Pharmacologic methods
 Herbal or vitamin supplements
 DMG, High dose vitamins, Mineral supplements
 Immune modulation
 Steroids, IVIg, antifungals, probiotics
 Chelation
(oral, transdermal, IV)
 Low Dose Naltrexone (LDN)

Non pharmacologic
 Dietary intervention
 Gluten & casein free (GFCF), Specific carbohydrate, Body
ecology
 Hyperbaric
Oxygen Therapy (H-BOT)
Traditional Pharmacologic Treatments

No known pharmacological treatment for core
deficits of autism.
 We
don’t know the neurochemistry!
 Every neurotransmitter has been implicated.

But until we figure it out we do symptom
modification.
 Target


symptoms
based on similarity to other psychiatric disorders.
those that interfere most with child’s activities (school,
therapies, home)
 Borrow
currently used medications
Data from IAN
Registry 2007-08 with
5181 children with
reported ASD
Usage is common
and increases with
age (Rosenberg et al 2010)
percent
Medication Usage in IAN Registry
80
70
60
50
40
30
20
10
0
ANY DRUG
3 OR MORE
0-18
0-2
3-5
6-11
12-17
age
35
STIMULANTS
30
NEUROLEPTICS
25
20
ANTIDEPRESSANT
15
ANTICONVULSANT/MOOD
STABILIZER
10
ALPHA AGONIST
5
0
0-18
0-2
3-5
6-11
12-17
Psychopharmacology



Goal: improve function without side effect
Rule out other causes (medical, environment)
Make sure other interventions are in place
 School
program & other therapies
 Medical care

Practicalities:
 Document
details of the symptom
 Start low, increase slowly
 Monitor closely and reassess over time
Unfortunate Truths

Only 2 medications currently are FDA approved for
children with autism

Both atypical neuroleptics – worst side effect profile!






risperidone & aripiprazole
can be associated with dsykinesias, cause significant weight gain,
hyperprolactinemia
need to monitor for metabolic syndrome: glucose (HbA1c or fasting
insulin), lipids, transaminases, CBC, prolactin
Most medication use is “off-label”
The more likely the medication is to be effective, the
more likely it is to have substantial side effects
Children with ASD are


Less likely to respond
More likely to have side effects
Meds matched to symptoms

Restricted interests/repetitive behaviors


Aggression/severe behavioral
dyscontrol/irritability



Atypical neuroleptics: risperidone*, aripiprazole*, ziprasidone,
olanzapine, quetiapine
Anti-convulsants: carbamazepine, valproate*, lamotrigine,*
leveteracitam*
Attention/hyperactivity




SSRIs: fluoxetine*, citalopram*, paroxetine, sertraline
Stimulants: methylphenidate*, dextroamphetamine
Alpha agonists: clonidine*, guanfacine*
Atomoxetine
Sleep

Melatonin*, clonidine, trazodone, remeron, (iron if ferritin <50)
* Those with some randomized placebo controlled data
Translational medicine and ASD
therapeutics

Novel therapies are showing some promise
 GABA
and glutamate agents (based on E/I imbalance
theory)
 Oxytocin (based on social affiliation theories)



Discovery of the underlying pathophysiology in
ASD is allowing identification of treatments to
target core deficits
Animal models of single gene disorders are
showing the ability to reverse deficits … even in
adult animals
Human trials are underway
GABA and glutamate agents

Old and new agents tested:
 Valproate
(GABA agonist)
 Memantine, D-cycloserine, dextromethorphan
(glutamate NMDA receptor antagonists)
 Arbaclofen (known GABA B agonist, ? glutamate
receptor modulator)


Fragile X trial (Berry-Kravis et al., 2012) found improvements
on a social avoidance scale. BUT … it failed to improve study’s
primary outcome (ABC-irritability)
Similar findings in sample of idiopathic ASD (unpublished data
from Seaside Therapeutics)
 Trials
of various agents are still underway
Oxytocin

The “pro-social” peptide
 IV

and intranasal preparations
Published trials showed improvement in number
of behaviors
 repetitive
behaviors, affective speech comprehension,
theory of mind, social learning, face processing
 some effects persisted beyond treatment period
(Hollander et al., 2003; Hollander et al., 2007; Andari et al., 2010 Guastella
et al., 2010; Anagnostou et al., 2012; Anagnostou et al., 2014)
Oxytocin

Small trial of intranasal
administration in 13 adults
with high functioning autism
(Andari et al., 2010)
neutral

Simulated “game of catch”
with one neutral player, one
good and one bad
 Then tested preferences for
each player & face
processing

Results showed:

enhanced ability to process
socially relevant cues
 increasing trust feelings
toward the good player
 Improved time spent
looking at socially relevant
part of face (eyes)
good
bad
subject
So … where are we?

What we know:






Autism is a neurological disorder
Genetic susceptibility
Prevalence is increasing
Increased co-morbidities (eg epilepsy)
Behavioral treatments proved efficacious
What we don’t know:






What is the neurological basis
Which genes are involved
Why prevalence is increasing
Which environmental factors
What is the significance of the co-morbidities
Which treatments are most beneficial for which individuals
For more information…

Autism information

Boston Children’s Hospital


Autism Consortium


http://www.cdc.gov/ncbddd/autism/index.html
Foundations





http://www.nimh.nih.gov/healthinformation/autismmenu.cfm
CDC


http://autismconsortium.org/
NIH


http://www.childrenshospital.org/health-topics/conditions/a/autismspectrum-disorders
http://www.autismspeaks.org/
http://www.autismsciencefoundation.org/
http://www.autism-society.org/site/PageServer
http://sfari.org/
Clinical trials

http://clinicaltrials.gov